This project develops a systems genetics approach using genetically defined recombinant inbred (Rl) rodent challenge models (collaborative cross mice-CC) that capture 90% of the natural genetic variation in the mouse, a unique resource capable of untangling polygenic, complex disease traits. This infection model will be coupled with genomics, proteomics, and reverse genetics and used as a platform technology to identify the virus-host interactions and susceptibility alleles that regulate highly pathogenic respiratory virus induced severe and end-stage lung disease in young and senescent animals. This platform will be used for a comparative pathogenomics approach focused on SARS-CoV, mouse-adapted influenza virus, and highly pathogenic avian influenza viruses. The goal is to compare and contrast the host susceptibility alleles and signaling circuitry that enhance pneumotropic virus replication and pathogenesis with the goal of identifying common key cellular targets that influence severe disease outcomes by diverse respiratory pathogens. To verify the importance of these alleles and signaling pathways in severe lung disease, we will model and empirically test disease outcomes using genetically defined virus mutants, siRNA knockdown techniques, CC recombinant inbred strains and select knockout animals. Finally, we evaluate the role of select common susceptibility alleles in siRNA-treated primates infected with SARS-CoV or high-path influenza viruses. Consequently, we will systematically test the hypothesis that genetic medicine and systems pathogenomics can predict disease outcomes in individuals, identify susceptibility alleles governing severe end-stage lung disease, uncover the role of specific viral genes in host signaling, and provide fundamental insights into the critical host circuitry that promotes efficient virus replication and virulence in the lung.